Charlwood, Joanne; (1998) Aberrant protein glycosylation in the carbohydrate-deficient glycoprotein syndromes and galactosaemia. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The carbohydrate-deficient glycoprotein syndromes (CDGS) and galactosaemia are autosomal recessive disorders of carbohydrate metabolism. They have been used in this study as tools to elucidate the mechanisms and consequences of defective glycosylation within the cell. This study demonstrates that seven of the eight CDGS type 1 patients studied have a deficiency of phosphomannomutase (PMM), the enzyme responsible for the conversion of mannose-6-phosphate into mannose-1-phosphate. This is believed to lead to a deficiency of GDP-mannose, dolichol-P-mannose and the lipid-linked-oligosaccharide precursor. The net effect of a deficiency of PMM is non-occupancy of glycosylation sites as demonstrated in the thesis by structural analysis of the glycans released from purified serum transferrin and cellular glycoproteins. The same non-occupancy of glycosylation sites has been found in the eighth CDGS type 1 patient who has normal phosphomannomutase activity. The development of the PMM assay has allowed both the identification of variants and the prenatal diagnosis of CDGS type 1 for couples at risk. Lysosomal enzymes have been used as model glycoproteins in which to study glycoprotein synthesis and targeting in cells with a defect in glycosylation. In galactosaemia a deficiency of galactose-1-phosphate uridyl transferase (GALT) leads to a build up of galactose-1-phosphate, which can be measured in red blood cells and is used to monitor the progress of treatment of patients on a galactose-free diet. The present investigation demonstrates that untreated patients have defective galactosylation of complex glycans in serum transferrin and cellular glycoproteins. Although the percentage of normally galactosylated glycans increases with treatment, some treated patients with low galactose-1-phosphate levels still have a large percentage of agalactosylated glycans in their serum transferrin. This discovery could explain the long term complications associated with galactosaemia and has implications in its treatment.

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